A cyclobutane indole derivative and its preparation method and application

Abstract

The present invention relates to the technical field of chemistry, and in particular to a cyclobutane indole derivative and a preparation method and application thereof. The method of the present invention comprises the steps of dissolving an indole compound or 5,6-dihydro-4H-pyrrolo[3,2,1-IJ]quinoline and a cyclobutene amide compound in an organic solvent, adding a catalyst and an additive, and reacting to obtain a cyclobutane indole derivative. The cyclobutane indole derivative of the present invention has an inhibitory effect on Siha cervical cancer cells, and its minimum IC 50 The value is 16.37uM; the preparation method provided by the present invention is simple to operate, has high atom economy, is environmentally friendly, and has good industrial application prospects.

Description

Technical Field

[0001] The present invention relates to the field of chemical technology, and in particular to a cyclobutane indole derivative and a preparation method and application thereof. Background Art

[0002] Cyclobutane is an important skeleton existing in many natural products and drug molecules. Hippolachnin A was isolated from a sponge in the South China Sea in 2013. It has strong antibacterial activity against three pathogens, Cryptococcus neformans, Trichophyton rubrum and gypseum, with a minimum inhibitory concentration of 0.41 μM. Introducing cyclobutane fragments into compounds with pharmacologically active fragments can increase the rigidity of their structure, giving them better in vivo stability and drug selectivity. For example, the hyperthermia drug lobaplatin, the antitumor drug combrestatin A4, the allosteric tyrosine kinase inhibitor NDI-034858, etc., all contain cyclobutane fragments. On the other hand, indole is a nitrogen-containing benzopyrrole alkaloid, including dihydroindole or indole ring structures, and most of its derivatives have certain physiological activities, such as antibacterial and anti-inflammatory, antihistamine, antiviral and anticancer pharmacological effects. Combining the rigid structure of the cyclobutane skeleton with a natural product fragment with pharmaceutical activity into a new cyclobutane indole skeleton is conducive to the discovery of new highly biologically active substances and is of great significance for the development of new drugs. Summary of the invention

[0003] In view of the above-mentioned deficiencies in the prior art, the present invention aims to provide a cyclobutane indole derivative and a preparation method and application thereof, so as to realize the application of the cyclobutane indole derivative in Siha cervical cancer.

[0004] In order to solve the above problems, the present invention adopts the following technical solutions:

[0005] In a first aspect, the present invention provides a cyclobutane indole derivative, the structural formula of the cyclobutane indole derivative is as follows:

[0006]

[0007] Among them, R 1 is hydrogen, alkoxy, alkyl, bis-naphthalene alcohol borate, phenyl alkynyl, methyl formate or halogenated hydrocarbon, R 2 is hydrogen or alkyl, R 3 is hydrogen or alkyl, R 4 AQ is a methyl group and has the following structural formula:

[0008]

[0009] In a second aspect, the present invention provides a method for preparing the cyclobutane indole derivatives, wherein an indole compound or 5,6-dihydro-4H-pyrrolo[3,2,1-IJ]quinoline and a cyclobuteneamide compound are dissolved in an organic solvent, a catalyst and an additive are added, and the cyclobutane indole derivatives are obtained after reaction.

[0010] As an implementation method, the additive includes acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, 2-methyl-2-phenylpropylcarboxylic acid, adamantanecarboxylic acid or Boc-L-valine.

[0011] As an implementation method, the organic solvent includes acetonitrile, N,N-dimethylformamide, ethylene dichloride, toluene, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether or hexafluoroisopropanol.

[0012] As an embodiment, the catalyst includes palladium acetate, palladium trifluoroacetate, palladium chloride, palladium (II) chlorobis (acetonitrile), bis (dibenzylideneacetone) palladium, 1,1-bis (diphenylphosphino) ferrocene palladium dichloride or tricyclohexylphosphine-(2'-amino-1,1'-biphenyl-2-yl) palladium (II) methanesulfonic acid.

[0013] As an implementable embodiment, the reaction temperature of the preparation method is 80 to 120° C., and the reaction time is 12 to 24 hours.

[0014] As an implementation method, the molar ratio of the indole compound to the cyclobuteneamide compound is 1 to 1.2:1; the molar ratio of the cyclobuteneamide compound to the catalyst is 1:0.05 to 0.2; the molar ratio of the cyclobuteneamide compound to the additive is 1:0.1 to 0.5; the amount ratio of the cyclobuteneamide compound to the organic solvent is 0.2 mmol:0.5 to 2 mL.

[0015] As a possible implementation method, the cyclobutane indole derivative obtained after the reaction is subjected to liquid extraction; the extractant used in the liquid extraction is ethyl acetate, the upper liquid is collected after extraction, dried with anhydrous sodium sulfate, the ethyl acetate is evaporated to obtain crude crystals, and the crude crystals are recrystallized and chromatographed on a 200-400 mesh silica gel column, and the eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:1-10.

[0016] In a third aspect, the present invention provides the use of the cyclobutane indole derivatives in the preparation of Siha cervical cancer therapeutic drugs.

[0017] As an embodiment, the IC of the cyclobutane indole derivative is 50 The value is not less than 16.37uM.

[0018] The beneficial effects of the present invention are as follows: the present invention utilizes indole compounds or 5,6-dihydro-4H-pyrrolo[3,2,1-IJ]quinoline and cyclobuteneamide compounds to prepare cyclobutane indole derivatives, thereby achieving inhibition of Siha cervical cancer cells; the preparation method of the present invention is simple to operate, has high atom economy, is environmentally friendly, and has good industrial application prospects. DETAILED DESCRIPTION

[0019] The present invention is further described in detail below in conjunction with specific embodiments.

[0020] It should be noted that these embodiments are only used to illustrate the present invention rather than to limit the present invention. Simple improvements to the method based on the concept of the present invention all fall within the scope of protection claimed by the present invention.

[0021] The preparation method of cyclobutane indole derivatives is as follows: an indole compound or 5,6-dihydro-4H-pyrrolo[3,2,1-IJ]quinoline and a cyclobutene amide compound are dissolved in an organic solvent, a catalyst and an additive are added, and the cyclobutane indole derivatives are obtained after reaction.

[0022]

[0023] The cyclobuteneamide compounds used in the examples can be synthesized with reference to the literature (J.Am.Chem.Soc.2019,141,10048-10059).

[0024] In the above formula, R1 is hydrogen, alkoxy, alkyl, Bpin, phenyl alkynyl, methyl formate, halogenated hydrocarbon; R2 is hydrogen, alkyl; R3 is hydrogen, alkyl; R4 is methyl. Indole can also be replaced by 5,6-dihydro-4H-pyrrolo[3,2,1-IJ]quinoline.

[0025] The additive includes acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, 2-methyl-2-phenylpropylcarboxylic acid, adamantanecarboxylic acid or Boc-L-valine.

[0026] The organic solvent includes acetonitrile, N,N-dimethylformamide, ethylene dichloride, toluene, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether or hexafluoroisopropanol.

[0027] The catalyst includes palladium acetate, palladium trifluoroacetate, palladium chloride, palladium (II) chlorobis (acetonitrile), bis (dibenzylideneacetone) palladium, 1,1-bis (diphenylphosphino) ferrocene palladium dichloride or tricyclohexylphosphine-(2'-amino-1,1'-biphenyl-2-yl) palladium (II) methanesulfonic acid.

[0028] Example 1

[0029] To a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100 ° C. under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a yellow liquid with a yield of 93%.

[0030] The reaction equation is as follows:

[0031]

[0032] The structural characterization data of the obtained target product are shown below:

[0033] 1 H NMR(400MHz,Chloroform-d)δ9.75(s,1H),8.83(dd,J=7.5,0.9Hz,1H),8.74(dd,J=4.2,1.5Hz,1H), 8.11(dd,J=8.3,1.5Hz,1H),7.65(d,J=7.9Hz,1H),7.53(t,J=7.9Hz,1H),7.50–7.43(m,1H),7.40(d d,J=8.3,4.2Hz,1H),7.33(d,J=8.2Hz,1H),7.29–7.20(m,1H),7.14–7.08(m,1H),6.95(s,1H),3.77 (s,3H),3.35(p,J=8.7Hz,1H),2.84(td,J=9.1,2.3Hz,2H),2.65(td,J=9.1,2.3Hz,2H),1.63(s,3H).

[0034] 13 C NMR(100MHz,Chloroform-d)δ174.1,148.1,138.4,138.1,136.6,134.7,128.1,127.7,126.4, 125.1,122.6,121.7,121.7,121.4,120.4,118.7,116.6,109.7,37.9,36.6,35.0,32.8,30.8.

[0035] HRMS(ESI)m / z calcd for C 24 H 24N3O[M+H] + 370.1914, found 370.1908.

[0036] The structure of the target compound is inferred from the above characterization data as follows:

[0037]

[0038] The antitumor activity of cyclobutane indole derivatives against Siha cervical cancer cells was evaluated by in vitro cell proliferation inhibition experiment (MTT method). The logarithmic phase cells were digested with trypsin, and centrifuged and collected after terminating the digestion to prepare a cell suspension; the prepared cell suspension was gently mixed, and 100 μL was added to each well of a 96-well culture plate, and the cell concentration of each well was 5000 (the edge wells were filled with sterile PBS), and the inoculated cell culture plate was placed in an incubator for culture until the cell monolayer adhered to the wall and grew, and the control group (blank control, negative control and positive control) and the drug group were divided, and 3-6 duplicate wells were set for each group. The blank control was a culture medium without tumor cells, the negative control was a culture medium containing tumor cells without drug addition, and the positive control was a cisplatin drug. The drug group was added with 6 concentration gradient compound solutions and cultured in an incubator. After 48 h of culture, MTT (20 μL) solution was added to each well and culture was continued for 4 h. Then the supernatant was discarded and DMSO (150 μL) solution was added. The cells were shaken on a shaker until the formazan in the cells was completely dissolved by DMSO. Then the absorbance (OD) of each well was measured using an enzyme-linked immunosorbent assay (ELISA).

[0039] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 >80uM.

[0040] Example 2

[0041] To a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100°C under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a yellow liquid with a yield of 78%.

[0042] The reaction equation is as follows:

[0043]

[0044] The structural characterization data of the obtained target product are shown below:

[0045] 1 H NMR(400MHz,Chloroform-d)δ9.78(s,1H),8.85(d,J=7.5Hz,1H),8.77(dd,J=4.1,1.4H z,1H),8.15(dd,J=8.2,1.2Hz,1H),8.11(s,1H),7.68(d,J=7.9Hz,1H),7.56(t,J=7.9Hz ,1H),7.52–7.48(m,1H),7.46–7.40(m,2H),7.26–7.25(m,1H),7.16–7.11(m,2H),3.36 (p,J=8.7Hz,1H),2.88(td,J=9.2,2.2Hz,2H),2.67(td,J=9.2,2.2Hz,2H),1.65(s,3H).

[0046] 13 C NMR(100MHz,Chloroform-d)δ174.2,148.1,138.3,137.4,136.8,134.6,128.2,127.7,126 .0,124.1,122.1,121.7,121.5,120.3,120.2,119.2,116.8,111.6,37.8,36.5,35.0,30.6.

[0047] HRMS(ESI)m / z calcd for C 23 H 22 N3O[M+H] + 356.1757, found 356.1753.

[0048] The structure of the target compound is inferred from the above characterization data as follows:

[0049]

[0050] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 >80uM.

[0051] Example 3

[0052] To a 25 mL Shrek tube, weighed 5,6-dihydro-4H-pyrrolo[3,2,1-IJ]quinoline (0.24 mmol), cyclobuteneamide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100°C under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a dark red liquid with a yield of 94%.

[0053] The reaction equation is as follows:

[0054]

[0055] The structural characterization data of the obtained target product are shown below:

[0056] 1 H NMR(400MHz,Chloroform-d)δ9.77(s,1H),8.84(d,J=7.6Hz,1H),8.76(dd,J=4.1,1.5Hz,1H) ,8.25–8.10(m,1H),7.56(t,J=7.9Hz,1H),7.52–7.46(m,2H),7.43(dd,J=8.2,4.2Hz,1H),7. 10–7.01(m,2H),6.95(d,J=7.0Hz,1H),4.16(t,J=5.7Hz,2H),3.38(p,J=8.7Hz,1H),3.02(t, J=6.0Hz,2H),2.86(td,J=9.2,2.0Hz,2H),2.65(td,2H),2.28(p,J=6.0Hz,2H),1.64(s,3H).

[0057] 13 C NMR(100MHz,Chloroform-d)δ174.1,148.2,138.5,136.4,135.4,134.8,128.0,127.5,123.8,122.8 ,122.3,122.1,121.6,121.4,119.1,118.6,117.8,116.4,44.0,38.0,36.5,35.2,30.7,24.9,23.0.

[0058] HRMS(ESI)m / z calcd for C 26 H26 N3O[M+H] + 396.2070, found 396.2068.

[0059] The structure of the target compound is inferred from the above characterization data as follows:

[0060]

[0061] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 >80uM.

[0062] Example 4

[0063] In a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100 ° C. under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a dark red liquid with a yield of 66%.

[0064] The reaction equation is as follows:

[0065]

[0066] The structural characterization data of the obtained target product are shown below:

[0067] 1H NMR(400MHz,Chloroform-d)δ9.89(s,1H),8.88(d,J=7.4Hz,1H),8.83(dd,J=4.2,1.5Hz,1H),8.61(s,1H),8.18(dd,J =8.2,1.3Hz,1H),7.59(d,J=8.1Hz,1H),7.55(d,J=5.7Hz,1H),7.52(d,J=7.1Hz,2H),7.47(dd,J=8.2,4.2Hz,1H),7.4 2–7.35(m,3H),7.38–7.31(m,1H),7.28(d,J=8.0Hz,1H),7.13(t,J=7.2Hz,1H),7.06(t,J=7.2Hz,1H),4.61(s,2H),3. 83(t,J=5.6Hz,2H),3.43–3.31(m,1H),3.18(t,J=11.0Hz,2H),3.06(t,J=5.6Hz,2H),2.90–2.77(m,2H),1.61(s,3H).

[0068] 13 C NMR(100MHz,Chloroform-d)δ174.5,148.1,138.4,137.9,136.5,135.4,134.7,132.0,128.7,128.0,128.0,127.9 ,127.6,126.5,121.6,121.3,120.9,120.2,119.6,118.7,116.5,110.7,73.5,69.9,38.2,36.7,36.3,30.8,27.3.

[0069] HRMS(ESI)m / z calcd for C 32 H 32 N3O2[M+H] + 490.2489, found 490.2482.

[0070] The structure of the target compound is inferred from the above characterization data as follows:

[0071]

[0072] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 It is 58.24uM.

[0073] Example 5

[0074] To a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100°C under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a yellow liquid with a yield of 85%.

[0075] The reaction equation is as follows:

[0076]

[0077] The structural characterization data of the obtained target product are shown below:

[0078] 1 H NMR(400MHz,Chloroform-d)δ9.78(s,1H),8.86(d,J=6.8Hz,1H),8.77(dd,J=4.2,1.5Hz,1H), 8.15(dd,J=8.3,1.4Hz,1H),8.07(s,1H),7.56(t,J=7.9Hz,1H),7.50(dd,J=8.3,1.1Hz,1H),7 .45(d,J=1.3Hz,1H),7.46–7.39(m,1H),7.31(d,J=8.3Hz,1H),7.09–7.05(m,2H),3.36(p,J=8 .7Hz,1H),2.87(td,J=9.0,2.3Hz,2H),2.67(td,J=9.2,2.3Hz,2H),2.50(s,3H),1.65(s,3H).

[0079] 13 C NMR(100MHz,Chloroform-d)δ174.2,148.2,138.4,136.5,135.7,134.7,128.4,128.1,127.6, 126.2,123.7,123.4,121.7,121.5,120.3,119.9,116.5,111.3,37.8,36.6,35.0,30.6,21.8.

[0080] HRMS(ESI)m / z calcd for C 24 H 24 N3O[M+H] +370.1914, found 370.1910.

[0081] The structure of the target compound is inferred from the above characterization data as follows:

[0082]

[0083] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 It is 16.37uM.

[0084] Example 6

[0085] To a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100 ° C. under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a colorless solid with a yield of 70%.

[0086] The reaction equation is as follows:

[0087]

[0088] The structural characterization data are as follows:

[0089] 1 H NMR(400MHz,Chloroform-d)δ9.78(s,1H),8.84(d,J=7.5Hz,1H),8.77(dd,J=4.2,1.5Hz,1H), 8.17(d,J=8.1Hz,1H),7.75(d,J=1.6Hz,1H),7.56(t,J=7.9Hz,1H),7.52–7.47(m,1H),7.45(dd ,J=8.2,4.3Hz,1H),7.32(dd,J=8.7,1.7Hz,1H),7.20(d,J=8.7Hz,1H),6.98(s,1H),3.77(s,3 H),3.35(p,J=8.7Hz,1H),2.81(td,J=9.2,2.3Hz,2H),2.65(td,J=9.1,2.3Hz,2H),1.60(s,3H)

[0090] 13C NMR(100MHz,Chloroform-d)δ173.9,147.9,136.6,134.4,128.1,127.9,127.6,126.2, 124.4,122.7,122.3,121.5,121.4,116.9,112.0,111.0,37.7,36.3,34.7,32.87,30.6.

[0091] HRMS(ESI)m / z calcd for C 24 H 23 BrN3O[M+H] + 448.1019, found 448.1014.

[0092] The structure of the target compound is inferred from the above characterization data as follows:

[0093]

[0094] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 >80uM.

[0095] Example 7

[0096] To a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100°C under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a yellow liquid with a yield of 45%.

[0097] The reaction equation is as follows:

[0098]

[0099] The structural characterization data are as follows:

[0100] 1H NMR(400MHz,Chloroform-d)δ9.87(s,1H),8.87(d,J=7.1Hz,1H),8.78(dd,J=4.3,1.5Hz,1H),8.26(s, 1H),8.20(d,J=8.0Hz,1H),7.88(s,1H),7.62–7.55(m,3H),7.55–7.50(m,1H),7.46(dd,J=8.3,4.3Hz, 1H),7.40(dd,J=8.4,1.2Hz,1H),7.38–7.36(m,1H),7.36–7.34(m,1H),7.34–7.28(m,2H),7.14(d,J=2 .3Hz,1H),3.40(p,J=8.7Hz,1H),2.87(td,J=9.1,2.2Hz,2H),2.69(td,J=9.2,2.2Hz,2H),1.65(s,3H).

[0101] 13 C NMR(100MHz,Chloroform-d)δ174.0,148.2,137.1,136.6,134.7,131.6,128.4,128.1,127.9,127.6,126.0 ,125.9,124.6,124.2,124.0,121.7,121.5,121.0,116.6,113.9,111.7,91.3,87.3,37.9,36.5,35.0,30.6.

[0102] HRMS(ESI)m / z calcd for C 31 H 26 N3O[M+H] + 456.2070, found 456.2066.

[0103] The structure of the target compound is inferred from the above characterization data as follows:

[0104]

[0105] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 >80uM.

[0106] Example 8

[0107] To a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100°C under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a yellow liquid with a yield of 53%.

[0108] The reaction equation is as follows:

[0109]

[0110] The structural characterization data are as follows:

[0111] 1 H NMR(400MHz,Chloroform-d)δ9.76(s,1H),8.84(d,J=7.4Hz,1H),8.77(dd,J=4.1,1.3Hz,1 H),8.20–8.11(m,2H),7.73(d,J=8.3Hz,1H),7.55(t,J=8.0Hz,1H),7.49(d,J=7.7Hz,1H),7 .43(dd,J=8.2,4.3Hz,1H),7.33(d,J=8.3Hz,1H),6.97(s,1H),3.79(s,3H),3.36(p,J=8.8H z,1H),2.88(td,J=9.2,2.0Hz,2H),2.69(td,J=9.3,2.1Hz,2H),1.66(s,3H),1.38(s,12H).

[0112] 13 C NMR(101MHz,Chloroform-d)δ174.1,148.1,140.0,138.4,136.6,134.7,133.5,130.2,128.5,128.1,12 8.0,127.6,126.1,125.2,123.4,121.6,121.4,116.6,109.0,83.5,38.1,36.6,35.1,32.8,31.0,25.0.

[0113] HRMS(ESI)m / z calcd for C 30 H 35 BN3O3[M+H] +496.2766, found 496.2764.

[0114] The structure of the target compound is inferred from the above characterization data as follows:

[0115]

[0116] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 It is 38.29uM.

[0117] Example 9

[0118] To a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100 ° C. under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a dark green liquid with a yield of 87%.

[0119] The reaction equation is as follows:

[0120]

[0121] The structural characterization data are as follows:

[0122] 1 H NMR(400MHz,Chloroform-d)δ9.77(s,1H),8.83(dd,J=7.5,1.1Hz,1H),8.76(dd,J=4.2,1.6Hz,1 H),8.15(dd,J=8.2,1.4Hz,1H),7.93(s,1H),7.55(t,J=7.9Hz,1H),7.50(dd,J=8.2,1.2Hz,1H),7 .44(dd,J=8.3,4.2Hz,1H),7.04(s,1H),7.00(d,J=2.3Hz,1H),6.92(s,1H),3.94(s,3H),3.92(s, 3H), 3.36 (p, J = 8.7Hz, 1H), 2.83 (td, J = 9.0, 2.3Hz, 2H), 2.65 (td, J = 9.1, 2.3Hz, 2H), 1.62 (s, 3H).

[0123] 13C NMR(100MHz,Chloroform-d)δ174.0,148.0,147.2,144.6,138.2,136.6,134.5,131.7,128.0,1 27.6,123.8,121.6,121.4,118.6,116.6,102.2,95.0,56.7,56.2,37.6,36.5,34.9,30.3,29.7.

[0124] HRMS(ESI)m / z calcd for C 25 H 26 N3O3[M+H] + 416.1969, found 416.1964.

[0125] The structure of the target compound is inferred from the above characterization data as follows:

[0126]

[0127] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 It is 26.34uM.

[0128] Example 10

[0129] To a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100°C under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and ethyl acetate (15 mL × 3) was used for extraction. The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain an orange liquid with a yield of 50%.

[0130] The reaction equation is as follows:

[0131]

[0132] The structural characterization data are as follows:

[0133] 1H NMR(400MHz,Chloroform-d)δ9.77(s,1H),8.83(dd,J=7.5,1.0Hz,1H),8.76(dd,J=4.2,1.6Hz,1H),8.45 (s,1H),8.18(d,J=0.8Hz,1H),8.15(dd,J=8.3,1.5Hz,1H),7.82(dd,J=8.4,1.3Hz,1H),7.68(d,J=8.4Hz ,1H),7.59–7.52(m,1H),7.50(dd,J=8.2,1.2Hz,1H),7.43(dd,J=8.3,4.2Hz,1H),7.29(d,J=2.4Hz,1H), 3.95(s,3H),3.35(p,J=8.7Hz,1H),2.86(td,J=9.1,2.3Hz,2H),2.69(td,J=9.1,2.2Hz,2H),1.63(s,3H).

[0134] 13 C NMR(100MHz,Chloroform-d)δ173.9,168.3,148.3,138.6,136.8,136.5,134.7,129.6,128.1,127 .6,124.7,123.8,123.6,121.7,121.5,120.3,119.8,116.5,114.0,52.1,37.8,36.4,35.0,30.5.

[0135] HRMS(ESI)m / z calcd for C 25 H 24 N3O3[M+H] + 414.1812, found 414.1808.

[0136] The structure of the target compound is inferred from the above characterization data as follows:

[0137]

[0138] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 >80uM.

[0139] Embodiment 11

[0140] In a 25 mL Shrek tube, weighed indole compound (0.24 mmol), cyclobutene amide compound (0.2 mmol), palladium acetate (0.02 mmol), acetic acid (0.1 mmol) and toluene (0.2 mL) were added in sequence, and the mixture was placed in an oil bath at 100°C under air conditions for sufficient reaction for 12 hours. After the reaction, a saturated ammonium chloride solution was used to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL × 3). The ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and concentrated in vacuo. The mixture was separated by silica gel column chromatography (gradient elution: petroleum ether / ethyl acetate = 10 / 1-4 / 1) to obtain a yellow liquid with a yield of 30%.

[0141] The reaction equation is as follows:

[0142]

[0143] The structural characterization data are as follows:

[0144] 1 H NMR(400MHz,Chloroform-d)δ9.76(s,1H),8.83(d,J=7.5Hz,1H),8.76(dd,J=4.2,1.5Hz,1H),8.16(d,J= 7.6Hz,1H),7.61(d,J=8.0Hz,1H),7.58–7.52(m,1H),7.52–7.47(m,1H),7.44(dd,J=8.2,4.2Hz,1H),7.34 (d,J=8.2Hz,1H),7.26–7.22(m,1H),7.10(t,J=7.3Hz,1H),6.98(s,1H),3.81(s,3H),3.34(p,J=8.8Hz,1 H), 2.77 (td, J = 9.0, 2.3Hz, 2H), 2.61 (td, J = 9.3, 2.3Hz, 2H), 1.98 (q, J = 7.3Hz, 2H), 0.66 (t, J = 7.3Hz, 3H).

[0145] 13 C NMR(100MHz,Chloroform-d)δ174.3,147.8,138.1,134.6,128.2,127.9,126.8,12 6.5,121.6,121.5,120.5,119.9,118.5,109.6,39.4,36.8,36.4,35.2,32.9,9.0.

[0146] HRMS(ESI)m / z calcd for C 25 H 26 N3O[M+H]+ 384.2070, found 384.2065.

[0147] The structure of the target compound is inferred from the above characterization data as follows:

[0148]

[0149] The compound has an inhibitory effect on Siha cervical cancer cells, IC 50 >80uM.

[0150] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention rather than to limit it. Although the present invention has been described with reference to the preferred embodiments of the present invention, it should be understood by those skilled in the art that various changes may be made in form and details without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A cyclobutane indole derivative, characterized in that: The structural formula of the cyclobutane indole derivative is as follows:

2. The method for preparing the cyclobutane indole derivative according to claim 1, characterized in that: The indole compound and the cyclobutene amide compound are dissolved in an organic solvent, a catalyst and an additive are added, and a cyclobutane indole derivative is obtained after reaction; The catalyst includes palladium acetate, palladium trifluoroacetate, palladium chloride, palladium (II) chlorobis (acetonitrile), bis (dibenzylideneacetone) palladium, 1,1-bis (diphenylphosphino) ferrocene palladium dichloride or tricyclohexylphosphine-(2'-amino-1,1'-biphenyl-2-yl) palladium (II) methanesulfonic acid; The additive includes acetic acid, trifluoroacetic acid, benzoic acid, p-toluenesulfonic acid, 2-methyl-2-phenylpropylcarboxylic acid, adamantanecarboxylic acid or Boc-L-valine.

3. The method for preparing a cyclobutane indole derivative according to claim 2, characterized in that: The organic solvent includes acetonitrile, N,N-dimethylformamide, ethylene dichloride, toluene, dimethyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether or hexafluoroisopropanol.

4. The method for preparing a cyclobutane indole derivative according to claim 2, characterized in that: The reaction temperature of the preparation method is 80-120° C., and the reaction time is 12-24 hours.

5. The method for preparing a cyclobutane indole derivative according to claim 2, characterized in that: The molar ratio of the indole compound to the cyclobuteneamide compound is 1-1.2:1; the molar ratio of the cyclobuteneamide compound to the catalyst is 1:0.05-0.2; the molar ratio of the cyclobuteneamide compound to the additive is 1:0.1-0.5; the dosage ratio of the cyclobuteneamide compound to the organic solvent is 0.2mmol:0.5-2mL.

6. The method for preparing a cyclobutane indole derivative according to claim 2, characterized in that: After the reaction, the cyclobutane indole derivative is obtained and then subjected to liquid phase extraction; the extractant used in the liquid phase extraction is ethyl acetate, the upper liquid is collected after extraction, dried with anhydrous sodium sulfate, and the ethyl acetate is evaporated to obtain crude crystals, which are recrystallized and chromatographed on a 200-400 mesh silica gel column, and the eluent is a mixed solution of ethyl acetate and petroleum ether in a volume ratio of 1:1-10.

7. Use of the cyclobutane indole derivative according to claim 1 in the preparation of Siha cervical cancer therapeutic drugs.

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